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1.
Clin Immunol ; 255: 109730, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37562724

RESUMEN

Aging is associated with bone marrow (BM) inflammaging and, in some individuals, with the onset of clonal hematopoiesis (CH) of indeterminate potential. In this study conducted on 94 strictly healthy volunteers (18 to 80 yo), we measured BM and peripheral blood (PB) plasma levels of 49 hematopoietic and inflammatory cytokines. With aging, 7 cytokines increased in BM (FLT3L, CXCL9, HGF, FGF-2, CCL27, IL-16, IL-18) and 8 decreased (G-CSF, TNF, IL-2, IL-15, IL-17A, CCL7, IL-4, IL-10). In PB, 10 cytokines increased with age (CXCL9, FLT3L, CCL27, CXCL10, HGF, CCL11, IL-16, IL-6, IL-1 beta, CCL2). CH was associated with higher BM levels of MIF and IL-1 beta, lower BM levels of IL-9 and IL-5 and higher PB levels of IL-15, VEGF-A, IL-2, CXCL8, CXCL1 and G-CSF. These reference values provide a useful tool to investigate anomalies related to inflammaging and potentially leading to the onset of age-related myeloid malignancies or inflammatory conditions.


Asunto(s)
Médula Ósea , Citocinas , Humanos , Interleucina-1beta , Interleucina-15 , Hematopoyesis Clonal , Interleucina-16 , Interleucina-2 , Factor Estimulante de Colonias de Granulocitos , Células de la Médula Ósea , Hematopoyesis
2.
J Cell Mol Med ; 25(20): 9557-9566, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34492730

RESUMEN

Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56-88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.


Asunto(s)
Cromosomas Humanos Par 12 , Cromosomas Humanos Par 4 , Predisposición Genética a la Enfermedad , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Translocación Genética , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Aberraciones Cromosómicas , Análisis Citogenético , Femenino , Estudios de Asociación Genética , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Trastornos Mieloproliferativos/mortalidad , Trastornos Mieloproliferativos/terapia , Pronóstico
3.
Pediatr Blood Cancer ; 68(7): e29071, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33871916

RESUMEN

Shwachman-Diamond syndrome with Shwachman-Bodian-Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Registry for Severe Chronic Neutropenia, three were identified with malignant solid tumors (ovary, breast, and esophagus). All cancers occurred during the fifth decade and, despite being localized at diagnosis, were rapidly fatal thereafter. No cancer was observed post transplantation in the 14 HSCT survivors. Based on the literature and our patient data, we can merely advance that this complication is predominantly diagnosed in adults.


Asunto(s)
Neoplasias , Neutropenia , Síndrome de Shwachman-Diamond , Femenino , Humanos , Neoplasias/complicaciones , Neoplasias/epidemiología , Neoplasias/genética , Neutropenia/epidemiología , Neutropenia/etiología , Neutropenia/genética , Sistema de Registros , Síndrome de Shwachman-Diamond/complicaciones
4.
Int J Mol Sci ; 19(12)2018 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-30513905

RESUMEN

Recent advances in the field of cancer genome analysis revolutionized the picture we have of acute myeloid leukemia (AML). Pan-genomic studies, using either single nucleotide polymorphism arrays or whole genome/exome next generation sequencing, uncovered alterations in dozens of new genes or pathways, intimately connected with the development of leukemia. From a simple two-hit model in the late nineties, we are now building clonal stories that involve multiple unexpected cellular functions, leading to full-blown AML. In this review, we will address several seminal concepts that result from these new findings. We will describe the genetic landscape of AML, the association and order of events that define multiple sub-entities, both in terms of pathogenesis and in terms of clinical practice. Finally, we will discuss the use of this knowledge in the settings of new strategies for the evaluation of measurable residual diseases (MRD), using clone-specific multiple molecular targets.


Asunto(s)
Células Clonales/patología , Hematopoyesis/genética , Leucemia Mieloide Aguda/genética , Neoplasia Residual/genética , Predisposición Genética a la Enfermedad , Humanos , Leucemia Mieloide Aguda/clasificación , Modelos Biológicos
5.
Transfusion ; 57(7): 1717-1723, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28439927

RESUMEN

BACKGROUND: Patients with hematologic malignancies are at high risk for both thrombosis and bleeding. During the prolonged periods of thrombocytopenia experienced by patients who are receiving intensive chemotherapy, clinicians often hesitate to prescribe any protection against thrombosis. In case of anticoagulant prescription, it is the prescribers' responsibility to weigh risks and benefits for each patient. Current guidelines exist but do not take into account types of thrombosis, patients' comorbidities, or previous bleeding events. STUDY DESIGN AND METHODS: We proposed to gain insight into hematologists' beliefs about antithrombotic prescription in hematologic malignancy patients, to design future clinical trials. Therefore, we conducted a survey in France to evaluate the practices among a panel of hematologists. RESULTS: We found that more than 92% of the respondents prescribed therapeutic anticoagulation in case of pulmonary embolism or deep venous thrombosis. In the case of therapeutic anticoagulation, only 64% of the physicians reconsidered treatment under a platelet threshold of 50 × 109 /L. None of the respondents decided to renounce treatment, nor to discontinue it because of thrombocytopenia, except in distal venous thrombosis or superficial vein thrombosis. One-fifth of clinicians proposed the insertion of a vena cava filter. CONCLUSION: As observed in the United States and Canada, we noticed discrepancies between recommendations and current practices in France. This highlights the urgent need to conduct studies to evaluate both efficacy and safety of antithrombotics in patients with hematologic cancer and thrombocytopenia.


Asunto(s)
Antineoplásicos/efectos adversos , Fibrinolíticos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Transfusión de Plaquetas , Trombocitopenia/terapia , Neoplasias Hematológicas/sangre , Humanos , Trombocitopenia/inducido químicamente
6.
Life Sci Alliance ; 7(8)2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38802246

RESUMEN

A continuous supply of energy is an essential prerequisite for survival and represents the highest priority for the cell. We hypothesize that cell differentiation is a process of optimization of energy flow in a changing environment through phenotypic adaptation. The mechanistic basis of this hypothesis is provided by the established link between core energy metabolism and epigenetic covalent modifications of chromatin. This theory predicts that early metabolic perturbations impact subsequent differentiation. To test this, we induced transient metabolic perturbations in undifferentiated human hematopoietic cells using pharmacological inhibitors targeting key metabolic reactions. We recorded changes in chromatin structure and gene expression, as well as phenotypic alterations by single-cell ATAC and RNA sequencing, time-lapse microscopy, and flow cytometry. Our observations suggest that these metabolic perturbations are shortly followed by alterations in chromatin structure, leading to changes in gene expression. We also show that these transient fluctuations alter the differentiation potential of the cells.


Asunto(s)
Diferenciación Celular , Cromatina , Metabolismo Energético , Células Madre Hematopoyéticas , Humanos , Diferenciación Celular/genética , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Cromatina/metabolismo , Cromatina/genética , Epigénesis Genética , Adaptación Fisiológica , Análisis de la Célula Individual/métodos
7.
Nat Commun ; 12(1): 5044, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-34413298

RESUMEN

Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS.


Asunto(s)
Mutación , Subunidades Ribosómicas Grandes de Eucariotas/metabolismo , Ribosomas/genética , Ribosomas/patología , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/patología , Adolescente , Adulto , Animales , Fenómenos Biológicos , Células Cultivadas , Niño , Preescolar , Dictyostelium , Drosophila , Factores Eucarióticos de Iniciación/genética , Factores Eucarióticos de Iniciación/metabolismo , Células Germinativas , Humanos , Lactante , Simulación de Dinámica Molecular , Factores de Elongación de Péptidos/genética , Factores de Elongación de Péptidos/metabolismo , Unión Proteica , Biosíntesis de Proteínas , Proteínas/genética , Proteínas/metabolismo , Ribonucleoproteína Nuclear Pequeña U5/genética , Ribonucleoproteína Nuclear Pequeña U5/metabolismo , Ribosomas/metabolismo , Saccharomyces cerevisiae , Homología de Secuencia de Aminoácido , Síndrome de Shwachman-Diamond/metabolismo , Adulto Joven
8.
Blood Adv ; 4(15): 3550-3557, 2020 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-32761230

RESUMEN

Clonal hematopoiesis (CH) of indeterminate potential has been described in blood samples from large series of patients. Its prevalence and consequences are still not well understood because sequencing methods vary and because most studies were performed in cohorts comprising individuals with nonhematologic diseases. Here, we investigated the frequency of CH in 82 paired bone marrow and blood samples from carefully selected healthy adult volunteers. Forty-one genes known to be mutated in myeloid malignancies were sequenced with a 1% threshold of detection. In bone marrow samples, clones were found in almost 40% of healthy volunteers more than 50 years old. The most frequent mutations were found in DNMT3A and TET2, with 1 individual carrying 3 variants. Variant allele frequencies were highly concordant between blood and bone marrow samples. Blood parameters were normal except for those in 2 individuals: 1 had a mild macrocytosis and 1 had a mild thrombocytosis. Furthermore, no morphologic abnormalities or dysplasia were detected when bone marrow smears were carefully evaluated. Individuals with CH differed from others by age (62.8 vs 38.6 years; P < .0001) and platelet count (294 vs 241 ×109/L; P = .0208), the latter being no more significant when removing the 2 individuals who carried the JAK2 p.V617F mutation. These results confirm that CH is a very common condition in healthy adults over 50 years old. Consequently, the detection of driver myeloid mutations should be interpreted with caution in the absence of cytologic abnormalities in the blood and/or the bone marrow.


Asunto(s)
Médula Ósea , Hematopoyesis Clonal , Adulto , Voluntarios Sanos , Hematopoyesis/genética , Humanos , Persona de Mediana Edad , Prevalencia
9.
BMC Res Notes ; 11(1): 436, 2018 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-29970140

RESUMEN

BACKGROUND: Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (SOS/VOD), is a potentially fatal complication of allogeneic or autologous hematopoietic stem cell transplantation. A plethora of transplant and patient-related risk factors predispose to SOS/VOD and should be taken into account for prognosis assessment as well as for adequate therapeutic intervention. CASE PRESENTATION: We describe the case of a mantle cell lymphoma patient who developed a fulminant hepatitis following oxaliplatin-containing intensive chemotherapy and autologous transplantation. This clinical manifestation was secondary to a very severe SOS/VOD. The patient did not exhibit the usual risk factors and presented a non-classical form with major cytolysis, thus puzzling SOS/VOD diagnosis in this context. CONCLUSION: SOS has been previously reported after oxaliplatin-based chemotherapy regimens for colorectal cancers, in particular in patients with colorectal liver metastases. We therefore suspected a potential relationship with oxaliplatin-based regimen as a driver of SOS/VOD in a non-susceptible lymphoma patient. With regards to this case, clinicians and especially intensivists should be aware of this atypical presentation.


Asunto(s)
Enfermedad Veno-Oclusiva Hepática/complicaciones , Hepatitis/etiología , Fallo Hepático Agudo/etiología , Trasplante de Células Madre de Sangre Periférica , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones
12.
Oncotarget ; 7(51): 85573-85583, 2016 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-27458168

RESUMEN

Peripheral T-cell lymphoma (PTCL) is a group of diseases with poor outcome and few therapeutic options. We aimed to assess the efficacy of bendamustine in real life cohort of patients.Between November 2009 and March 2015, 138 PTCL patients were treated with bendamustine in 27 centers. Population median age was 64 (28-89) years with male/female ratio of 1.4. There were mainly angio-immunoblastic (AITL = 71), PTCL-not otherwise specified (PTCL-NOS = 40) and anaplastic large cell lymphoma (ALCL = 8). The majority of patients (96%) had disseminated disease and extranodal localizations (77%). Median number of chemotherapy lines prior to bendamustine was 2 (1-8). Median duration of response (DoR) after the last chemotherapy prior to bendamustine was 4.3 months (1-70) and 50% of patients had refractory disease.Median number of administered bendamustine cycles was 2 (1-8) and 72 patients (52%) received less than 3 mostly because of disease progression. Median dose was 90 (50-150) mg/m². Overall response rate (ORR) was 32.6% with complete response (CR) rate of 24.6% and median DoR was 3.3 months (1-39). AITL patients were more sensitive than PTCL-NOS patients (ORR: 45.1 versus 20%, p = 0.01). Median PFS and OS were 3.1 (0.2-46.3) and 4.4 (0.2-55.4) months. On multivariate analysis, refractory disease (p = 0.001) and extranodal localization (p = 0.028) adversely influenced ORR. Grade 3-4 thrombocytopenia, neutropenia and infections were reported in 22, 17 and 23% of cases respectively.Bendamustine as single agent could be considered as a therapeutic option for relapsed or refractory PTCL, particularly in chemosensitive or AITL patients. Combinations of bendamustine with other drugs warrant further evaluation.


Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Clorhidrato de Bendamustina/administración & dosificación , Linfoma de Células T Periférico/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/efectos adversos , Clorhidrato de Bendamustina/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Francia , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Metástasis Linfática , Linfoma de Células T Periférico/mortalidad , Linfoma de Células T Periférico/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento
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